Spelling suggestions: "subject:"parkinson\'s disease"" "subject:"parkinson\'s adisease""
511 |
Evaluation of gene transfer strategies using recombinant adeno-associated viruses for Parkinson's disease cell and gene therapy / Evaluation de stratégies de transfert de gènes via les virus adéno-associés recombinants pour la thérapie génique et cellulaire de la maladie de ParkinsonBockstael, Olivier 08 September 2010 (has links)
La maladie de Parkinson se caractérise entre autres par une dégénérescence progressive des neurones dopaminergiques de la substance noire pars compacta (SNpc) qui innervent le striatum. Cette dégénération entraîne une baisse de la sécrétion de dopamine dans le striatum qui est responsable de la majorité des symptômes moteurs de la maladie de Parkinson. Plusieurs approches ont été étudiées pour le traitement de la maladie de Parkinson :i) restaurer une synthèse de dopamine dans le striatum par une greffe striatale de neurones dopaminergique ou par un transfert striatal de gènes impliqués dans la synthèse de la dopamine ;ii) protéger et stimuler les neurones dopaminergiques survivants dans la substance noire pars compacta des patients ;iii) corriger les déséquilibres de la boucle motrice engendrés par la baisse de stimulation dopaminergique du striatum ;iv) stimuler et recruter des progéniteurs cérébraux pour les faire se différencier en neurones dopaminergiques dans le striatum. Toutes ces approches thérapeutiques peuvent impliquer des transferts de gènes.<p>Les vecteurs dérivés des virus adéno-associés (rAAV) constituent des outils de choix pour le transfert de gènes dans les tissus cérébraux. Par ailleurs, de nombreuses applications nécessitent une régulation de l’expression du transgène. Nous disposons au laboratoire d’un vecteur rAAV inductible à la tétracycline (rAAV-TetON).<p>Nous décrivons dans ce travail :<p> i) le comportement du vecteur rAAV dérivé du sérotype 1 d’AAV utilisant la cassette d’expression TetON (rAAV2/1-TetON) comparé à celui du rAAV2/1 utilisant un promoteur constitutif pour l’expression du transgène (rAAV2/1-pCMV) dans le striatum et le mésencéphale (contenant la substance noire). A l’aide d’un vecteur rAAV2/1-TetON exprimant le GDNF, nous montrons que nous pouvons moduler le niveau d’expression du transgène dans le striatum par la dose d’inducteur administré aux animaux. Par ailleurs, nous montrons que le rAAV2/1-TetON présente dans le striatum une efficacité de transduction moindre que le rAAV2/1-pCMV mais qu’il présente un profil de biosécurité supérieur au rAAV2/1-pCMV car il limite fortement l’expression du transgène hors du striatum. De plus, le rAAV2/1-TetON n’entraîne pas de recrutement de lymphocytes T ni d’activation de la microglie dans le striatum. Lorsqu’il est injecté dans le mésencéphale, le vecteur rAAV2/1-TetON, contrairement au rAAV2/1-pCMV présente une expression préférentielle dans les neurones dopaminergiques de la SNpc et de l’aire tégmentale ventrale (VTA).<p>ii) le comportement des vecteurs rAAV2/1-pCMV et scAAV2/1-pCMV (vecteur « self-complémentaire » permettant une expression du transgène indépendamment de la synthèse du second brin du génome viral) dans la région neurogénique de la zone sous-ventriculaire (ZSV). Nous avons montré que les vecteurs rAAV2/1 infectent efficacement la ZSV et s’y expriment rapidement. Les vecteurs scAAV2/1 s’expriment plus rapidement dans la ZSV que les vecteurs rAAV2/1 (expression maximum à 24h et 48h, respectivement). De plus, les vecteurs rAAV2/1 présentent une efficacité de transfection importante pour les progéniteurs neuraux en prolifération (cellules C, transient amplifying progenitors) et les neuroblastes en migration (cellules A) mais pas pour les cellules souches neurales (cellules B). Nous observons, par ailleurs, que les rAAV2/1 induisent une baisse transitoire de la prolifération de la ZSV. Cet effet est indépendant de l’expression du génome et dépend donc probablement de la capside virale de nos vecteurs. De plus, cette baisse de prolifération n’induit pas d’apoptose. A long terme, nous observons des cellules exprimant le transgène dans la zone granulaire du bulbe olfactif, indiquant que la transduction des progéniteurs de la ZSV n’interfère pas avec leurs capacités de migration et de différenciation.<p>iii) l’efficacité de différents sérotypes de rAAV pour le transfert de gènes dans les cellules progénitrices neurales (NPC) in vitro. Nous avons montré que les rAAV peuvent transduire des NPC mais que l’efficacité spécifique des différents sérotypes testés varie en fonction de la région du cerveau fœtal et de l’espèce dont les NPC sont issues. Par ailleurs, les rAAV induisent une réduction drastique de la prolifération des cultures de NPC dépendante du sérotype de rAAV utilisé mais pas de l’origine fœtale des NPC ou de l’espèce dont elles sont issues.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished
|
512 |
Validating the National Institutes of Health Brief Fatigue Inventory and Characterizing Fatigue Symptoms across Patient PopulationsMartinez-Kaigi, Valerie T 08 1900 (has links)
A gold standard measurement does not exist to assess fatigue symptoms across patient populations. Current tools only consist of self-report measures that may not assess fatigue objectively. The National Institutes of Health-Brief Fatigue Inventory (NIH-BFI) is a clinician-administered instrument developed as a more objective assessment of fatigue symptoms. This study assessed the NIH-BFI's validity in diverse clinical populations, which included patients diagnosed with a mood disorder, Parkinson's disease, cancer, and healthy controls. Results suggest good criterion-related and convergent validity for the NIH-BFI. Results also indicate significant differences in fatigue severity between cohorts. Moreover, the data also suggest significant differences among groups in depression, anxiety, pain catastrophizing, sleep quality, global mental and physical health, and cognitive functioning. This study proposes that the NIH-BFI is a valid clinician-administered measure of fatigue that can be administered in multiple clinical populations.
|
513 |
Optimised label-free biomarker assays with electrochemical impedance spectroscopyXu, Mengyun January 2013 (has links)
There is huge academic interest and clinical need associated with the development of biomarker immunoassays where general aims are the generation of highly specific, convenient and sensitive sensing formats. In this project, a powerful electrochemical technique, electrochemical impedance spectroscopy (EIS), is applied in the establishment of powerful biomarker detecting protocols. Firstly, ultrasensitive, label-free and reusable insulin sensors, based on an antibody-PEGylated thiol self-assembly monolayer (PEG thiol SAM) interface, were produced and characterised via Faradaic EIS, presenting a detection limit (LOD) of 1.2 pM, a linear range across four orders of magnitude, and high sensitivity in even 50 % serum. By applying similar surface chemistry, a label-free biosensor, specific for the detection of α-synuclein antibodies, was fabricated. The α-synuclein interfaces used enabled the reliable detecting of this biomarker in patient sample serum. The concentration levels in the control and a patient group were determined to be significantly different, and, significantly, this difference was consistently across two different cohorts. Strikingly, this could potentially underpin an entirely new means of early Parkinson’s disease (PD) diagnosis. Non-Faradaic EIS methods were additionally applied to label-free insulin assays at both PEG thiol SAM and zwitterionic polymer film interfaces. The latter presented not only an exceptionally non-fouling interface, but also one seemingly both highly biocompatible and facilitating enhanced receptor: target binding. Finally, impedance assays, though potent, generally, operate by sampling only one of a limited number of available experimental variables, typically, Rct for Faradaic EIS, or C or Z for non-Faradaic EIS. Work carried out herein also explores the generation and utility of a portfolio of mathematically derived immittance functions all obtained from the same raw data sets. A particular focus was the examination of whether these were capable of increasing assay sensitivity and efficiency above normal impedance treatments.
|
514 |
Computational study of the mechanisms underlying oscillation in neuronal locomotor circuitsMerrison-Hort, Robert January 2014 (has links)
In this thesis we model two very different movement-related neuronal circuits, both of which produce oscillatory patterns of activity. In one case we study oscillatory activity in the basal ganglia under both normal and Parkinsonian conditions. First, we used a detailed Hodgkin-Huxley type spiking model to investigate the activity patterns that arise when oscillatory cortical input is transmitted to the globus pallidus via the subthalamic nucleus. Our model reproduced a result from rodent studies which shows that two anti-phase oscillatory groups of pallidal neurons appear under Parkinsonian conditions. Secondly, we used a population model of the basal ganglia to study whether oscillations could be locally generated. The basal ganglia are thought to be organised into multiple parallel channels. In our model, isolated channels could not generate oscillations, but if the lateral inhibition between channels is sufficiently strong then the network can act as a rhythm-generating ``pacemaker'' circuit. This was particularly true when we used a set of connection strength parameters that represent the basal ganglia under Parkinsonian conditions. Since many things are not known about the anatomy and electrophysiology of the basal ganglia, we also studied oscillatory activity in another, much simpler, movement-related neuronal system: the spinal cord of the Xenopus tadpole. We built a computational model of the spinal cord containing approximately 1,500 biologically realistic Hodgkin-Huxley neurons, with synaptic connectivity derived from a computational model of axon growth. The model produced physiological swimming behaviour and was used to investigate which aspects of axon growth and neuron dynamics are behaviourally important. We found that the oscillatory attractor associated with swimming was remarkably stable, which suggests that, surprisingly, many features of axonal growth and synapse formation are not necessary for swimming to emerge. We also studied how the same spinal cord network can generate a different oscillatory pattern in which neurons on both sides of the body fire synchronously. Our results here suggest that under normal conditions the synchronous state is unstable or weakly stable, but that even small increases in spike transmission delays act to stabilise it. Finally, we found that although the basal ganglia and the tadpole spinal cord are very different systems, the underlying mechanism by which they can produce oscillations may be remarkably similar. Insights from the tadpole model allow us to predict how the basal ganglia model may be capable of producing multiple patterns of oscillatory activity.
|
515 |
Dopamine Induced Post-Translational Modifications of α-Synuclein and the Role of Arsenic in the Development of Parkinson's Disease and Other SynucleinopathiesCholanians, Aram B. January 2016 (has links)
Synucleinopathies are a family of neurodegenerative diseases, with the distinctive pathological feature of Lewy bodies, which include Parkinson’s disease. Lewy bodies are intracellular inclusions filled with α-synuclein, a small neuronal protein with prion-like properties. The main function of α-synuclein is not fully understood, however, it plays a major role in disease progression. Dopamine interactions with α-synuclein have also been implicated in the progression of Parkinson’s disease. Dopamine crosslinks α-synuclein and causes generation of toxic oligomeric species of the protein. Little is known about dopamine-α-synuclein adducts, and one section of the current dissertation focuses on dopamine, levodopa, and α-synuclein interactions. Studies detailed herein demonstrated that lysine residues on α-synuclein have an essential role in the dopamine-induced oligomer formation. Evidence is also presented showing that removal of one of the reactive sites on dopamine by N-acetylcysteine and/or glutathione inhibits dopamine-induced oligomer formation, although the dopamine thiol-conjugates still bind to α-synuclein. In contrast, thiol-conjugates of the dopamine precursor levodopa, significantly increase α-synuclein oligomer formation. The data demonstrate the importance of the scavenging of dopamine and levodopa quinones by N-acetylcysteine and glutathione, and the subsequent changes in the interaction with α-synuclein and its oligomeric states. Environmental factors are key players in the development of synucleinopathies. Although arsenic pesticide exposure has been linked to elevated risk of Parkinson’s disease, there is a paucity of information on arsenic-induced pathological changes, which may be attributed to the onset of neurodegenerative processes. SH-SY5Y cells exposed to environmentally relevant levels of arsenic for 72 hours, develop α-synuclein oligomers and exhibitaugmented expression of stress markers. Thus, there is an increase in autophagy markers and other stress markers, including the accumulation and co-localization of LC3, major autophagy marker, and α-synuclein. Animals transiently exposed to arsenic through drinking water for 2 or 5 weeks, exhibited pathological features resembling synucleinopathies. Although animals were exposed at two-months of age and remained exposure free up to geriatric age (18 months), they still exhibited accumulation of α-synuclein and elevations in autophagy markers. The results demonstrated how even a short period of exposure to a toxicant can have detrimental neurological effects, which may contribute to the development of neurodegenerative disease years after exposure.
|
516 |
An investigation into the molecular aetiology of Parkinson's disease in South African patientsGlanzmann, Brigitte 03 1900 (has links)
Thesis (MScMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Parkinson's disease (PD) is a severely debilitating neurodegenerative disorder that results in
motor circuit dysregulation and ultimately, causes impairment of movement. This condition
is due to the selective degradation of the dopaminergic neurons in the substantia nigra pars
compacta in the midbrain, which subsequently results in the pathological symptoms namely
bradykinesia, resting tremor, postural instability and rigidity. It was initially hypothesized
that individuals who develop PD were exposed to an environmental trigger(s) that caused the
onset of the disease, but more recently, a significant genetic component, coupled to
environmental factors have been implicated in disease pathogenesis. Currently, there are
eight genes (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 and VPS35) that have
been directly implicated in PD.
Worldwide, the prevalence of neurodegenerative disorders is increasing as populations are
living longer. In Europe, Canada and USA, it has been projected that the prevalence of PD
may increase by a factor of two between 2010 and 2050; approximately a 92% increase. In
Tanzania (the only study done in sub-Saharan Africa) an even larger increase of 184%
between 2005 and 2025 is predicted, due to the fact that the speed of populations ageing in
developing countries, will exceed that of developed countries. Research into the causes and
risk factors underlying neurodegenerative disorders such as PD is therefore urgently needed
for policy makers and governments in developing nations to take appropriate action to deal
with this impending health care problem.
The aim of the present study was to investigate the molecular aetiology of a group of South
African PD patients. A total of 262 patients from various ethnic backgrounds were recruited
for the study, and 35% had a positive family history of PD with the average age at onset
(AAO) being 54.3 years of age (SD = 12.5 years). Mutation screening of the known PD
genes (Parkin, PINK1, LRRK2, SNCA and DJ-1) was performed using high resolution melt
and Sanger sequencing. Genotyping was done using fluorescently-labelled PCR primers
followed by electrophoresis on an ABI 3130xl genetic analyser (for CTG repeats in JPH3)
and with a KASP™ Genotyping Assay (for a 16bp indel in DJ-1). In order to identify a
novel PD-causing gene, whole exome sequencing (WES) was conducted on three Afrikaner
probands with an Illumina Genome Hiseq 2000TM and the sequences were aligned using the NCBI Human Reference Genome 37.2. The BORG (Bio-Ontological Relationship Graph)
semantic database, which models the relationship of human and model organism genes to
functions, pathways and phenotypes, was used to filter and prioritise genetic variants shared
between the three PD exomes.
It was determined that the known PD genes do not play a significant role in disease
pathogenesis in the South African patients as only 15/262 (5.7%) of the patients harboured
mutations: seven in Parkin, one in PINK1, six in LRRK2 and one in SNCA. Only one of the
patients harboured a 16bp indel variant at the transcription start site of DJ-1. None of the
Black PD patients had pathogenic repeat expansions in JPH3 thereby excluding Huntington
disease-like 2 as a cause of the disease phenotype.
Genealogical analysis revealed that six of the apparently unrelated Afrikaner PD probands
were related to a founder couple that immigrated to South Africa in the 1600s which suggests
that there is a possible founder effect for the disease. Bioinformatics analysis of WES data
on three of the probands identified 21 variants in 12 genes that were present in all three PD
exomes and fulfilled various criteria. Sanger sequencing was used for verification of five
variants and of these, two (in CDC27 and NEDD4) were found to be artefacts. The
remaining three (in HECDT1, TBCC and RNF40) were excluded based on the lack of cosegregation
with disease and the high frequency of the allele in controls. Further work is
necessary to verify the presence of the remaining sixteen variants and to characterise each of
them for their possible pathogenicity.
The discovery of novel PD-causing genes is important as this may shed light on the pathways
or processes that are involved. A current hypothesis implicates the lysosome-dependent
pathway as a unifying biochemical pathway that can account for the phenotypic spectrum
within PD. Notably, although Mendelian forms are thought to account for only about 10-
15% of cases, the study of Mendelian inherited variants is likely to provide insight into the
pathophysiology of the more common sporadic form of this condition. Dissecting the key
molecular mechanisms underlying PD will provide critical information for improved
treatment strategies and drug interventions that will ultimately prevent or halt neuronal cell
loss in susceptible individuals. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is 'n erge neurodegeneratiewe bewegings-siekte, wat motorstroombaan
disregulasie veroorsaak. Dit lei uiteindelik tot beperkte bewegings vermoëns. Hierdie toestand
word veroorsaak weens die selektiewe agteruitgang van die dopaminergeniese neurone in die
substantia nigra pars compacta in die midbrein, wat later lei tot die patologiese simptome
naamlik: bradykinesia, rustende spiersametrekkings, posturale onstabiliteit en rigiditeit. Daar is
aanvanklik vermoed dat individue wat PS ontwikkel, aan 'n omgewingsfaktor(e) blootgestel is
wat die aanvang van die siekte veroorsaak het, terwyl meer onlangs is daar 'n aansienlike
genetiese komponent tesame met omgewingsfaktore geïdentifiseer, wat betrokke is by die
patogenese van die siekte. Tans is daar agt gene (Parkin, PINK1, LRRK2, SNCA, DJ-1,
ATP13A2, EIF4G1 en VPS35) wat direk by PS geïmpliseer is.
Wêreldwyd is daar ‗n toenemende voorkoms van neurodegeneratiewe siektes aangesien
bevolkings langer leef. In Europa, Kanada en die VSA, is daar geprojekteer dat die voorkoms
van PS tussen 2010 en 2050 met 'n faktor van twee verhoog kan word. Dit is ongeveer 'n 92%-
verhoging. In Tanzanië (die enigste studie wat tot dusver in sub-Sahara Afrika gedoen is) word
daar selfs ‗n groter toename, van 184% tussen 2005 en 2025 voorspel. Dit is te danke aan die feit
dat die bevolkings- veroudering in ontwikkelende lande die van ontwikkelde lande sal oorskry.
Ondersoeke na die oorsake en risiko-faktore onderliggend aan neurodegeneratiewe siektes,
byvoorbeeld PS, word dus dringend benodig deur beleidmakers en regerings in ontwikkelende
lande, sodat hulle die nodige stappe kan neem om hierdie dreigende gesondheidsorg-probleem op
te los.
Die doel van die huidige studie was om ondersoek in te stel na die molekulêre etiologie van 'n
groep Suid-Afrikaanse PS pasiënte. 'n Totaal van 262 pasiënte van verskillende etniese
agtergronde, is gewerf vir die studie. Hiervan het 35% 'n positiewe familiegeskiedenis van PS en
die gemiddelde aanvangs ouderdom (AAO) was 54,3 jaar (SD = 12,5 jaar). Mutasie-analise van
die bekende PS gene is uitgevoer met behulp van hoë resolusie smelt en Sanger
volgordebepaling. Genotipering is gedoen met behulp van fluoresserend geëtiketteerde PKR
inleiers met elektroforese, op 'n ABI 3130xl genetiese analiseerder (CTG herhalings in JPH3), en
met 'n KASP ™ Genotipering toets (vir 'n 16bp indel in DJ-1). Ten einde, om 'n nuwe PSveroorsakende
geen te identifiseer was heel eksoom volgordebepaling (WES) uitgevoer op drie
Afrikaner PS positiewe pasiënte met 'n Illumina Genome Hiseq 2000™ en die volgorders is gerangskik met behulp van die NCBI Menslike Verwysings Genoom 37.2. Die BORG (Bio-
Ontologiese Verhoudings Grafiek) semantiese databasis, wat gebaseer is op die verhouding van
die mens en model organisme gene funksies, paaie en fenotipes, en is gebruik om genetiese
variante, wat gedeel word tussen die drie PS exome te filtreer en te prioritiseer.
Daar is vasgestel dat die bekende PS gene nie 'n belangrike rol in die patogenese van die siekte
in die Suid-Afrikaanse pasiënte speel nie. Dit is aangesien slegs 15/262 (5.7%) van die pasiënte
bekende mutasies dra: sewe in Parkin, een in PINK1, ses in LRRK2 en een in SNCA. Slegs een
van die pasiënte het 'n 16bp delesie variant in die transkripsie promotor area van DJ-1 gedra.
Geen van die Swart PS pasiënte het patogeniese herhalings in JPH3 vertoon nie. Gevolglik is
Huntington siekte-agtige 2 uitgesluit as 'n oorsaak van die siekte fenotipe.
Genealogiese analise het getoon dat ses van die skynbaar onverwante Afrikaner PS pasiënte
verwant is aan 'n stigter paartjie wat in die 1600's na Suid-Afrika geïmigreer het, wat daarop dui
dat daar 'n moontlike stigter effek vir die siekte is. Bioinformatiese analise van WES data vir drie
van die pasiënte, het 21 variante in 12 gene geïdentifiseer, wat in al drie PS exome teenwoordig
was en verskeie kriteria vervul het. Sanger volgordebepaling is gebruik vir die bevestiging van
vyf variante en van hierdie, is twee (in CDC27 en NEDD4) bevind om artefakte te wees. Die
oorblywende drie (in HECDT1, TBCC en RNF40) is uitgesluit gebaseer op die gebrek aan
gesamentlike-segregasie met die siekte en die hoë frekwensie van die allele in die kontrole groep.
Verdere werk is nodig om die teenwoordigheid van die oorblywende variante te verifieer en om
elkeen van hulle te karakteriseer vir hulle moontlike patogenisiteit.
Die ontdekking van die nuwe PS-veroorsakende gene is belangrik aangesien dit lig kan werp op
die stelsels of prosesse wat betrokke is. 'n Huidige hipotese impliseer die lisosoom-afhanklike pad
as 'n verenigende biochemiese padweg, wat verantwoordelik is vir die fenotipiese spektrum binne
PS. Alhoewel Mendeliese vorms vermoedelik verantwoordelik is vir slegs omgeveer 10-15% van
die gevalle, is die studie van Mendelse gene geneig om insig te verkry in die patofisiologie van
die meer algemene sporadiese vorm van hierdie toestand. Ontleding van die kern molekulêre
meganismes onderliggend aan PS sal kritiese inligting vir beter strategieë vir behandeling en
geneesmiddel-intervensies voorsien, wat gevolglik neuronale sel verlies in vatbare individue sal
voorkom of beëindig. / Medical Research Council / National Research Foundation / Harry Crossley Foundation
|
517 |
Tiefe Hirnstimulation des Nucleus subthalamicus: Die Rolle der intraoperativen Makrostimulation in Bezug auf präoperative Planung und postoperatives motorisches / nichtmotorisches Outcome / Deep brain stimulation of the subthalamic nucleus: The role of intraoperative macrostimulation relating to preoperative planings and postoperative motoric / nonmotoric outcomePinter, Anabel 20 July 2016 (has links)
No description available.
|
518 |
Investigating the relationship between stressful life events, coping style and Parkinson's diseaseUnderwood, Helen January 2011 (has links)
Section A gives an overview of Parkinson’s disease (PD), followed by a review of physiological and psychological literature suggestive of a relationship between stress and illness, with special consideration given to neurological disorders, including PD. Literature suggestive of direct and moderating relationships of coping style in relation to illness is then given. Finally, implications of the literature and directions for future research are considered. Section B describes an empirical study. Objectives. Literature suggests that a relationship exists between stressful life events (SLEs), coping style and illness. The present study aimed to investigate the direct relationships between both SLEs and coping style, and PD, and coping style as a moderator between SLEs and PD. Design. A retrospective, correlational design was employed in the current pilot study, using correlational and multivariate methods of analysis. Methods. Life-time experience of SLEs and coping style were measured using self-report questionnaires, and were completed by a group of people with PD (N = 19) and a group of people without PD (N = 20). Results. Significant relationships were found between SLEs and PD, and emotion-oriented coping and PD. People who reported a higher number of SLEs were associated with a 2.6 times higher risk of having PD (OR = 2.60; 95% CI, 1.35 – 4.99) and those who reported a higher level of emotion-oriented coping had an 8% increased chance of having PD (OR = 1.08; 95% CI, 1.00 – 1.17), compared to those with fewer reported SLEs. No other significant direct effects or moderator effects were found. Conclusions. These findings suggest an association between stressful life events and PD, and to a lesser degree between emotion-oriented coping and PD. Further research is needed to replicate and clarify findings. Section C provides a critical appraisal of the study described in Section B. It addresses four questions posed with regard to: research skills and abilities learned, what could be done differently and why, clinical implications, and future research ideas. This section also includes personal reflection by the author of the process of carrying out the study, and of several learning points that occurred throughout the process.
|
519 |
The Present, A Thousand Times DeeperTalley, Edie 16 December 2016 (has links)
The creative nonfiction essays and poetry in this collection explore family survival during the hardest of times--when the desire to give up is at its greatest--as told from the perspective of a woman who is a daughter, sister, wife, mother, and grandmother. These are not stories of defeat. Nor are they merely explorations of death and dying. They are cleebrations of living, of surviving, of loving and being loved against all odds.
|
520 |
Network pharmacology of the MPP+ cellular model of Parkinson's diseaseKeane, Harriet January 2015 (has links)
Parkinson's disease (PD) is an incurable neurodegenerative motor disorder caused by the inexorable loss of dopamine neurones from the substantia nigra pars compacta. Cell loss is characterised by the perturbation of multiple physiological processes (including mitochondrial function, autophagy and dopamine homeostasis) and much of this pathophysiology can be reproduced in vitro using the mitochondrial toxin MPP+ (1-methyl-4-phenylpyridinium). It was hypothesised that MPP+ toxicity could be modelled using protein-protein interaction networks (PPIN) in order to better understand the interplay of systems-level processes that result in eventual cell death in MPP+ models and PD. Initially, MPP+ toxicity was characterised in the human, dopamine-producing cell line BE(2)-M17 and it was confirmed that the neurotoxin resulted in time and dose dependent apoptosis. A radio-label pulse-chase assay was developed and demonstrated that MPP+ induced decreased autophagic flux preceded cell death. Autophagic dysfunction was consistent with lysosome deacidification due to cellular ATP depletion. Pertinent PPINs were sampled from publically available data using a seedlist of proteins with validated roles in MPP+ toxicity. These PPINs were subjected to a series of analyses to identify potential therapeutic targets. Two topological methods based on betweenness centrality were used to identify target proteins predicted to be critical for the crosstalk between mitochondrial dysfunction and autophagy in the context of MPP+ toxicity. Combined knockdown of a subset of target proteins potentiated MPP+ toxicity and the combined resulted in cellular rescue. Neither of these effects was observed following single knockdown/overexpression confirming the need for multiple interventions. Cellular rescue occurred via an autophagic mechanism; prominent autophagosomes were formed and it was hypothesised that these structures allowed for the sequestration of damaged proteins. This thesis demonstrates the value of PPINs as a model for Parkinson's disease, from network creation through target identification to phenotypic benefit.
|
Page generated in 0.054 seconds